Schizophrenia and bipolar disorder are chronic debilitating disorders that affect 1-3% of the population. The etiology of these disorders is completely unknown. Disrupted in Schizophrenia-1 (DISC1) was identified as the gene that was disrupted on chromosome 1 in a Scottish family with a high concordance of major psychiatric disorders and a balanced translocation between chromosomes 1 and 11. Karyotyping has been done on five generations of this family and 18 of the 29 members with this translocation have schizophrenia, recurrent major depression, or bipolar disorder. This type of near Mendelian segregation for psychiatric disorders indicates an integral role for DISC1 in maintaining mental health and that disruption of DISC1 functions plays a role in the etiology of psychiatric disorders. Indeed, DISC1 mouse models exhibit behavioral abnormalities reminiscent of human disease phenotypes such as hyperlocomotion, increased depressive-like behavior, decreased sociability and working memory. Several of these mouse models also display brain pathology indicative of impairment in brain development. Recently, we reported that DISC1 regulates the proliferation of neural progenitors during embryonic brain development and adult neurogenesis. Furthermore, we discovered that DISC1 regulated neural progenitor proliferation by positively regulating the Wnt signaling pathway by acting as an inhibitor of GSK32, a pleiotropic protein serine/threonine kinase that triggers the degradation of 2-catenin. In the dentate gyrus, DISC1 loss of function causes reduced proliferation of adult neural progenitors, which is accompanied by behavioral consequences including hyperactivity and increased depressive-like behavior. The adult neurogenesis defects and abnormal behavior were reversed upon treatment with a GSK3 chemical inhibitor. Our results indicate that DISC1 plays an important role in controlling GSK32/2-catenin activity, which in turn impacts neurogenesis and psychiatric-related behaviors. In this application, we propose to decipher how DISC1 mutant variants may alter the role of DISC1 in Wnt signaling and neurogenesis. We plan to take a multidisciplinary approach by performing studies with mouse cell and in vivo models, as well as including experiments using human cells to analyze Wnt signaling and neural progenitor development. Furthermore, we will use chemical-genetic approaches to identify and characterize small-molecule probes for conditional and selective modulation of the DISC1/GSK32-Wnt/2-catenin pathway. These studies will ultimately enable a better understanding of the relationship between human genetic variation in DISC1 and the effects on neurogenesis, as well as to lead to a better understanding of the causes and treatment of neuropsychiatric disease. PUBLIC HEALTH RELEVANCE: The overall goals of this project are to determine if human DISC1 variants affect Wnt signaling and the development of neural stem cells, and to use chemical-genetic approaches to identify and characterize small molecule probes for conditional and selective modulation of the DISC1/GSK3beta/Wnt signaling pathway. We believe that this project will allow us to gain further insight into how genetic variation in DISC1 affects Wnt signaling in human cells, which is imperative to clarifying how DISC1 and Wnt signaling contribute to psychiatric disease. Furthermore, discovering small molecules that can bind and modulate DISC1 activity will not only provide novel tools to study the function of human DISC1, but will also serve as a platform from which to create novel therapeutics aimed at modulating the function of DISC1 in the Wnt signaling pathway.